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21.
Hans Gelderblom Ramon Salazar Jaap Verweij George Pentheroudakis Maja J A de Jonge Martin Devlin Christel van Hooije Francis Seguy Rosendo Obach Joan Pru?onosa Paola Principe Chris Twelves 《Clinical cancer research》2003,9(11):4101-4107
PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability. 相似文献
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Terezija M HrŽenjak Maja PopoviĆ Ljerka TiŠka-rudman 《Pathology oncology research : POR》1998,4(3):206-211
u-PA is secreted by the most malignant tumors. As a response to u-PA synthesis surrounding cells synthetize inhibitors of
plasminogen activators for tissue protection. Plasminogen activators were found also in earthworm tissue. From the tissue
homogenate of earthworm Eisenia foetida the glycolipoprotein mixture named G-90 was isolated. It contains two serine proteases
(P I, P II) with fibrinolytic and anticoagulative activities. The fibrinolytic activity of G-90, P I and P II was tested in
an in vitro euglobulinic test applied to fibrin clot from blood plasma of patients suffered from malignant tumors. G-90 and
above-mentioned proteases applied in this study showed euglobulinic time proportionally with the concentrations of added substances.
The influence of G-90 on the fibrinolysis rate does not depend only on its concentration, but depends too on histological
type of tissue (organ) where the malignant tumors are located. Enzyme P I and P II do not show this activity. 相似文献
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Aleksandar Raskovic Vida Jakovljevic Momir Mikov Maja Gavrilovic 《European journal of drug metabolism and pharmacokinetics》2004,29(2):83-86
A study was made of the combined effect of two commercial products of Stevia rebaudiana Bertoni and sodium monoketocholate (mkc) on blood glucose concentration in mice. One group of animals was treated four days with mkc, 4 mg/kg, s.c., second with 200 mg/kg, i.p., of Stevita (Stevita Co, INC, Arlington, Texas) (stevia), third with 20 mg/kg, i.p., of Clear Steviosides Liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), fourth with the combination of stevia and mkc, and the fifth with stevisode and mkc. Blood glucose concentration was measured before treatment, after the first and fourth dose, as well as after subjecting animals to glucose-tolerance test (500 mg/kg, p.o.) or provoking glycemia by injecting adrenaline (0.2 mg/kg, s.c.). It was found that one dose of stevioside combined with mkc caused a significant increase of glycemia with respect of mkc alone and control (10.80:7.90:8.01). However, when repeated four days, the same pretreatment resulted in a significant decrease of glycemia compared with single-dose pretreatment (10.80:7.20). The increase in glycemia with the mice that received four doses of stevioside and mkc and then were subjected to glucose-tolerance test was significantly lower compared to that in mice that were pretreated four days only with mkc before receiving glucose (6.33:7.80). Analogous difference was observed between the animals given mkc alone and mkc plus stevioside after injecting adrenaline (13.33:10.54). As for the interaction of mkc and stevia it was found that the combined pretreatment yielded lower values of glycemia compared with that measured after treatment with stevia alone (6.40:7.82). 相似文献
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Left atrial phasic function and heart rate variability in patients with systemic sclerosis: A new part of the old puzzle
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GeneYenta: A PhenotypeBased Rare Disease Case Matching Tool Based on Online Dating Algorithms for the Acceleration of Exome Interpretation
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Michael M. Gottlieb David J. Arenillas Savanie Maithripala Zachary D. Maurer Maja TarailoGraovac Linlea Armstrong Millan Patel Clara van Karnebeek Wyeth W. Wasserman 《Human mutation》2015,36(4):432-438
Advances in next‐generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontologybased semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. 相似文献
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Brandstetter Susanne Pawellek Maja Böhmer Merle M. Köninger Angela Melter Michael Kabesch Michael Apfelbacher Christian 《Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz》2022,65(12):1281-1288
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Mit Beginn der Impfkampagne hat eine neue Phase der Bewältigung der Coronapandemie begonnen. Zulassung und Empfehlung... 相似文献
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